Recent evidence demonstrates an essential role for cellular cathepsins in viral glycoprotein processing and cellular entry for the highly pathogenic viruses Ebola, SARS, coronavirus and Nipah/Hendra. Cathepsin L appears to be important for SARS CoV and Nipah virus glycoprotein activation while Ebola requires both cathepsins L and B for viral entry. Inhibitors of these enzymes effectively block viral entry and replication in cell culture. This proposal will build upon these new findings and will develop cathepsin inhibitors as therapeutics for these diverse viral agents. To accomplish this goal we propose the following aims: Specific Aim 1) Utilize high throughput screening of diverse libraries to identify cathepsin inhibitors. Specific Aim 2) Test the candidate compounds for inhibition of viral entry using a rapid, quantitative and safe assay employing viral pseudotypes carrying the glycoproteins of Ebola, SARS CoV, or Hendra virus. Confirm the inhibitory effect on replication of SARS CoV and a model coronavirus, mouse hepatitis virus (MHV). Specific Aim 3) Test the cathepsin inhibitors identified in Aims 1 and 2 in animal model systems using SARS CoV and MHV. In conclusion, the proposed work will produce candidate molecules for treatment of infection by viruses such as Ebola, SARS CoV and Hendra. [unreadable] [unreadable] [unreadable]